The present inventors have discovered a substantial body of evidence for the occurrence of oxidant injury in neurodegenerative and cardiovascular diseases, in particular Alzheimer's disease (AD) and ventricular fibrillation (VF), by demonstrating overproduction of isoprostanes (IsoPs) and neuroprostanes (NeuroPs). IsoPs and NeuroPs are prostaglandin-like compounds produced by free radical induced peroxidation of arachidonic acid (AA) and docosahexaenoic acid (DHA), respectively. Isoketals (IsoKs) and neuroketals (NeuroKs) are highly reactive γ-ketoaldehydes produced by the IsoP and NeuroP pathways, respectively. IsoKs and NeuroKs rapidly adduct to lysyl residues of proteins and also exhibit a unique and remarkable proclivity to crosslink proteins.
The present invention encompasses discoveries from studies both in brains from patients with Alzheimer's disease (AD) and an animal model of age-related dementia relevant to AD, ApoE null mice overexpressing human ApoE4.
Thus, an aspect of the present invention is identification of proteins adducted by IsoKs and NeuroKs in brains from patients with AD and the mouse model of AD dementia. Furthermore, the present invention demonstrates the relationship between onset of behavioral abnormalities and the occurrence of oxidative stress and IsoK/NeuroK adduct formation in the mouse model. Thus, the ability of selected antioxidants to suppress oxidative injury and IsoK/NeuroK adduct formation and improve behavioral abnormalities in these mice is determined.
Additionally, another aspect of the present invention is a novel pharmacologic intervention with pyridoxamine (PM), that preferentially intercepts and prevents IsoKs/NeuroKs from adducting to proteins in vitro, to prevent IsoK/NeuroK adduct formation and improve behavioral abnormalities in these mice. In this regard, suppression of oxidative stress in general and specifically suppression of IsoK/NeuroK adduct formation is a valuable strategy to mitigate the progression of neurodegeneration and dementia in neurological diseases associated with oxidative stress, such as AD.
Oxidative stress plays a fundamental role in the pathogenesis of such diseases, which leads to the formation of IsoKs and NeuroKs that adduct to and alter the function of critical cellular proteins. This in turn also impairs proteasomal degradation of adducted proteins and inhibits proteasome function, causing neuronal dysfunction and death resulting in dementia.
